Ongoing epidemiological studies by the Centers for Disease Control estimate that greater than 60% of the adult US population may be categorized as either overweight or obese [1]. The incidence of obesity is even greater in the VA population, with current estimates suggesting that over 72% of veterans may be classified as obese or overweight [2]. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). One of the neurological complications of obesity is an increased risk of developing co-morbidities like depressive illness. In obesity phenotypes, plasma leptin is increased but leptin transport across the blood-brain barrier (BBB) is impaired, suggesting that brain leptin resistance may be a mechanistic link between obesity and major depressive illness. This leptin resistance may be related to a combination of decreased leptin BBB transport and reduced leptin receptor (LepR) signaling. The overarching hypothesis of this proposal is that brain leptin resistance represents a mechanistic link in the etiology and progression of co-morbid depression in obesity. This hypothesis will be tested in two innovative experimental models of obesity: a novel antagonist that selectively blocks BBB transport of leptin and using a lentivirus vector that selectively downregulates hypothalamic insulin receptor expression (hypo-IRAS). In Aim 1 we will examine the ability of a leptin receptor antagonist (LRA) that impairs BBB leptin transport and creates a CNS leptin deficient state to elicit depressive-like and anxiety-like behaviors. We will also examine whether these behavioral changes are reversible. Using our hypo-IRAS model of obesity, we will assess whether decreases in brain leptin levels and LepR signaling are responsible for the development of depression-like behaviors in hypo-IRAS rats (Aim 2). In Aim 3, we will test the hypothesis that food restriction restores BBB transport of leptin and LepR-mediated signaling, thereby reversing the depressive-like phenotype observed in hypo-IRAS rats. In Aim 4, we will examine the ability of a drug that has been extensively studied in VA patients, namely gemfibrozil, to reverse behavioral despair and anhedonia in obese rodents. Successful completion of these studies will directly test our hypothesis that CNS leptin resistance elicits the development of depressive-like behaviors, which would enhance our understanding of the mechanisms through which reductions in body weight and normalization of metabolic parameters have positive effects on mood and anxiety measures in obese individuals. Most importantly, our studies will examine the ability of lifestyle and pharmacological interventions to reverse the depression-like phenotypes in obese rodents. Such findings would be directly translatable to VA patient populations.